Enantioselective approach to butenolides upon reduction of alkoxycarbene complexes of chromium with chiral dihydropyridines

Article abstract of DOI:10.1016/S0040-4039(01)00997-2

Chromium alkoxycarbene complexes tethered to a triple bond react with a series of chiral dihydropyridines, among which is N-methyl-1,2-dihydronicotine, to give enantioselectively, upon cascade insertion reactions, polycyclic butenolides.

Full text of DOI:10.1016/S0040-4039(01)00997-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5235–5237
Enantioselective approach to butenolides upon reduction of
alkoxycarbene complexes of chromium with chiral
dihydropyridines
Henri Rudler,* Andre´e Parlier, Victor Certal and Jean-Cedric Frison
Laboratoire de Synthe`se Organique et Organome´tallique, UMR 7611, Universite´ Pierre et Marie Curie, Tour 44-45,
4 place Jussieu Case 181, 75252 Paris Cedex 5, France
Received 11 May 2001; accepted 11 June 2001
Abstract—Chromium alkoxycarbene complexes tethered to a triple bond react with a series of chiral dihydropyridines, among
which is N-methyl-1,2-dihydronicotine, to give enantioselectively, upon cascade insertion reactions, polycyclic butenolides. © 2001
Elsevier Science Ltd. All rights reserved.
The enantioselective formation of organic compounds
via non-chiral carbene fragments from Fischer carbene
complexes has only met, up to now, with very limited
transformations: indeed, only an early example in
which the metal bore, besides the carbene, a chiral
phosphine, described the synthesis of optically active
cyclopropanes upon its interaction with an olefin.1,2
protonation at the ring junction, each operation leading
to a new stereocenter.
We felt that such a transformation was ideally suited
for attempts to an enantiomeric approach to buteno-
lides, on the one hand by the use of chiral reducing
agents, which would parallel the biomimetic reduction
of carbonyl compounds with NADPH and its mod-
els,11–13 on the second hand, by carrying out enantiose-
lective protonations.
Very recently, we discovered a new application of Fis-
cher carbene complexes for the synthesis of a broad
spectrum of butenolides 3 via the intramolecular incor-
poration of a triple bond and two CO ligands, induced
by the metal, and triggered by dihydropyridines
(Scheme 1).3–6 The key steps in these transformations
are a hydride transfer from N-methyldihydropyridines
to the carbene carbon of the various complexes 1
leading first to metal pyridinium alkylates 2, and a final
The reasons behind our expectations were the follow-
ing: first, a wealth of chiral dihydropyridines are known
to reduce enantioselectively carbonyl compounds. Sec-
ond, the dihydronicotines 5 and 7, easily obtained from
(S)-(−)-nicotine 4 reacted like simple dihydropyridines
with alkoxycarbene complexes 8 to give, in the case of
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00997-2

5236
H. Rudler et al. / Tetrahedron Letters 42 (2001) 5235–5237
Typically, when a dichloromethane solution of complex
10a was subjected to (S)-(1-phenylethyl)-1,4-dihydropy-
ridine 14 at −40°C, then slowly heated to room temper-
ature over 12 h, the butenolide 11a was indeed obtained
as a single isomer, in 62% yield but, according to chiral
GC, as a racemic mixture. Moving to the isomeric
1,2-dihydropyridine 15 an encouraging enantioselection
(ee, 27%) was observed. Similarly, the use of the chiral
dihydronicotinamide 16, a close analog of the natural
dihydropyridines, led indeed to the expected butenolide
in 55% yield, but again with a disappointing 4% ee.
Since the best result was observed for a dihydropyridine
in which the chiral center is b with respect to the
transferable hydride, we attempted the reaction with
the chiral N-methyl-1,2-dihydronicotine 7: under simi-
lar conditions as for N-methyldihydropyridine, the
butenolide 11a could be isolated as a single isomer
with, according to chiral GC, an enantiomeric excess of
33%. This excess increased to 55% when 10c was used
instead. As can be seen, the same behavior was
observed for all the complexes examined so far.
Scheme 1.
5, upon transfer of a hydride, the expected, stable
dihydronicotinium ylid complexes 9.3
The purpose of this communication is thus to report on
the enantiodifferentiating reductions of a series of car-
bene complexes leading to optically active butenolides.
It appears first that whereas the nature of the sub-
stituent on the triple bond is of no influence on the
enantiomeric excess, the nature of the substituent on
the carbene carbon is fundamental. Second, according
to these preliminary results (not optimized), the yields
of butenolides are lower in most of the cases, but for
10a, when compared to the yields observed for the same
reactions with N-methyldihydropyridine.2,7,10
High diastereoselectivity for the reduction of carbene
complexes 10 with N-methyl dihydropyridines had
already been established.3 This was impressively confir-
med in the case of complexes 12a and 12b which led
diastereospecifically to 13a and 13b in 74 and 53% yield,
respectively. Compound 13a was fully characterized by
an X-ray structure analysis.7
A common feature for all the transformations depicted
herein is the creation of two new contiguous stereocen-
ters upon addition of a hydride and a proton as the
initiator and the terminator of the cascade insertions.
This leads, in the general case, stereospecifically to the
more stable products in which the heterocyclic ring
substituents are trans and in equatorial positions. In the
case of the chiral dihydropyridines, one can assume
that the enantiomeric differentiation is the result of the
formation of two diastereomeric intermediates upon
interaction of the carbene complexes and the dihy-
dropyridines prior to the hydride transfer. Such inter-
mediates would thus mimic the ternary complexes
ketone:dihydropyridine:Mg2+ which have been put to
the fore in the case of the enantiomeric reductions of
ketones by NADPH and its models.11–13 An important
point seems to arise from these preliminary results, the
These and previous results, urged us to carry out the
same transformations with the aforementioned chiral
dihydropyridines 7, but also with the dihydropyridines
14, 15 and 16 prepared according to the literature.8,9

H. Rudler et al. / Tetrahedron Letters 42 (2001) 5235–5237
5237
distance between the hydride to be transferred and the
chiral center since 1,2-dihydroprydines are more
efficient in terms of enantioselectivity than 1,4-dihy-
dropyridines. Such an observation had already been
made for the enantioselective reduction of carbonyl
compounds with NADH mimics, and confirms again
the parallel which exits between carbonyl compounds
and carbene complexes.
for example: Weyershausen, B.; Do¨tz, K. H. Eur. J.
Inorg. Chem. 1999, 1057; (g) Ja¨kel, C.; Do¨tz, K. H.
Tetrahedron 2000, 56, 2167; (h) For relative asymmetric
syntheses of polycyclic systems, see: Yan, J.; Zhu, J.;
Matasi, J. J.; Herndon, J. W. J. Org. Chem 1999, 64,
1291.
3. Rudler, H.; Parlier, A.; Certal, V.; Vaissermann, J.
Angew. Chem., Int. Ed. 2000, 39, 3417.
4. Rudler, H.; Parlier, A.; Durand-Re´ville, T.; Martin-Vaca,
B.; Audouin, M.; Garrier, E.; Certal, V.; Vaissermann, J.
Tetrahedron 2000, 56, 5001.
5. Rudler, H.; Parlier, A.; Martin-Vaca, B.; Garrier, E.;
Vaissermann, J. J. Chem. Comm. 1999, 1439.
6. For other examples of multiple CO and alkyne insertion
reactions, see: (a) Semmelhack, M. F.; Tamura, R.;
Schnatter, W.; Springer, J. J. Am. Chem. Soc. 1984, 106,
6363; (b) Yao-Chang, X.; Challener, C. A.; Dragisich, V.;
Brandvold, T. A.; Peterson, G. A.; Wulff, W. D. J. Am.
Chem. Soc. 1989, 111, 7269; (c) Bao, J.; Wulff, W. D.;
Dragisich, V.; Wenglowsky, S.; Ball, R. G. J. Am. Chem.
Soc. 1994, 116, 7616.
Modification of the structure of the reducing agents
(e.g. of dihydronicotine) or the use of related more
elaborate dihydropyridines along with attempts at car-
rying out enantioselective protonations are in progress
and might be ways to improve the encouraging enan-
tioselectivities already observed in these cascade
insertions.
Acknowledgements
The authors are indebted to Dr. S. Thorimbert (Univer-
sity P. M. Curie, Paris) and Professor J. C. Cherton
(University Versailles) for their assistance in the ee
determinations by GC and HPLC.
7. Crystal data for 13a: C23H22O3, space group P212121,
,
Z=4, Mo Ka radiation (u=0.71069 A), a=9.145(2),
3
,
,
b=10.484(4), c=19.256(6) A, V=1846(1) A , refinement
on F2, R(F)=5.36%, wR(F2)=5.80%, GOF=1.13 for
236 parameters and 1514 unique reflections with (Fo)2>
1.5s(Fo)2.
References
8. (a) Wong, Y.-S.; Marazano, C.; Gnecco, D.; Das, B. C.
Tetrahedron Lett. 1994, 35, 707; (b) Mehmandoust, M.;
Marazano, C.; Singh, R.; Gillet, B.; Cesario, M.; Four-
rey, J.-L.; Das, B. C. Tetrahedron Lett. 1988, 29, 4423; (c)
Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco,
D.; Das, B. C. Synlett 1992, 431.
9. Combret, Y.; Torche´, J.-J.; Ple´, N.; Duflos, J.; Dupas, G.;
Bourguignon, J.; Que´guiner, G. Tetrahedron 1991, 47,
9369.
1. Cooke, M. D.; Fischer, E. O. J. Organomet. Chem. 1973,
56, 279.
2. For references on reactions involving either chiral com-
plexes or chiral substrates, see: (a) Wulff, W. D.
Organometallics 1998, 17, 3116; see also: (b) Hegedus, L.
S. J. Am. Chem. Soc. 1982, 104, 5538; Lugan, N.; Kelley,
C.; Terry, M. R.; Geoffroy, G. L.; Rheingold, A. L. J.
Am. Chem. Soc. 1990, 112, 3220; (c) Brookhart, M.;
Timmers, D.; Tucker, J. R.; Williams, G. D.; Husk, G.
R.; Brunner, H.; Hammer, B. J. Am. Chem. Soc. 1983,
105, 6721; (d) Soderberg, B. C.; Hegedus, L. S.; Sierra,
M. A. J. Am. Chem. Soc. 1990, 112, 4364; (e)
Bouancheau, C.; Parlier, A.; Rudler, M.; Rudler, H.;
Vaissermann, J.; Daran, J. C. Organometallics 1994, 13,
4708; (f) For carbene complexes derived from sugars, see
10. The low yield for complexes in which R1=Me is mainly
due to their decomposition by a-elimination.
11. Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1.
12. Leroy, C.; Levacher, V.; Dupas, G.; Que´guiner, G.; Bour-
guignon, J. Tetrahedron: Asymmetry 1997, 19, 1109.
13. Ohno, A.; Oda, S.; Ishikawa, Y.; Yamazaki, N. J. Org.
Chem. 2000, 65, 6381.
.